Pharmacology- Chen Flashcards
1
Q
What does the thyroid produce?
A
Thyroid hormones:
Thyroxine (T4)
Triiodo-thyronin (T3)
Reverse Triiodothyronin (rT3)
2
Q
What 2 things do thyroid hormones regulate?
A
- Growth and development (CNS)
2. Maintain Metabolic homeostasis in adults
3
Q
What does deficiency of thyroid hormones lead to?
A
Cretinism- Mental retardation and dwarfism
4
Q
What metabolic things do thyroid hormones regulate?
A
- Calorigenesis: Temp regulation
- CV effects: Increased B receptor sensitivity
- Normal respiration
- Erythropoiesis
- Cholesterol metabolism
5
Q
Follicular cells concentrate what via the Na/I symptorter?
A
Iodide
6
Q
What catalyzes the covalent binding of I with tyrosine residures on thyroglobulin (TG) in the process of organification
A
Thyroid peroxidase
7
Q
What forms monoiodinated tyrosine (MIT)?
A
Adding 1 I to tyrosine
8
Q
What forms diiodinated tyrosine (DIT)?
A
Adding 2 I to tyrosine
9
Q
What does thyroid peroxidase catalyze on thyroglobulin?
A
Covalent association of MIT and DIT into T3 and T4
-This is coupling and is stored as colloids
10
Q
What is the ratio of T4 to T3 within thyroglobulin?
A
5:1
11
Q
What happens upon stimulation by TSH?
A
Follicular cells endocytose colloid into lysosomes to yield free T3 and T4, which are released into circulation
12
Q
What % if bound to thyroid binding globulins and albumin?
A
99%
13
Q
What is the half life of T4?
A
6 days
14
Q
What is the half life of T3?
A
1 day
15
Q
Where is T4 converted to T3?
A
Peripheral tissues
16
Q
How many times more potent is Te than T4?
A
4X
17
Q
What yields free I for new thyroid hormone synthesis?
A
Uncoupled DIT and MIT are deoidinated intracellularly to yield free I
18
Q
During peripheral metabolism at target tissue what happens to T4?
A
It is deiodinated by 5’-deiodinases present in target tissues and liver
19
Q
What produces biologically active T3?
A
If iodine is removed from the outer ring
20
Q
What produces biologically inactive rT3?
A
If iodine is removed from the inner ring
21
Q
Tell me the relationship between thyroid-pituitary-tissues and feedback
A
TRH stimulates the release of TSH, which stimulates adenylyl cyclase-mediated mechanism in the thyroid to increase synthesis and release of T3 and T4, which negatively feeds back to inhibit actions of TRH on pituitary gland and inhibit synthesis and secretion of TRH in hypothalamus
22
Q
How does thyroid hormone enter cells?
A
Passively or through active transport
23
Q
What kind of domains does the thyroid hormone receptor contain?
A
Thyroid-hormone binding, DNA-binding, dimerization domain
24
Q
What are 2 other components of thyroid-hormone receptors?
A
TRa and TRb
25
What does thyroid-hormone receptors form homodimers and heterodimers with?
Retinoid X receptor
26
In absence of T3 or T4, thyroid hormone receptors bind to what and suppress gene transcription?
Corepressors
27
What does binding of T3 and T4 promote?
Dissociation of corepressor and recruitment of coactivator to the DNA to activate gene transcription
28
Most common cause of hypothyroidism?
Hashimoto's thyroiditis
29
Symptoms of Hashimoto's Thyroiditis?
Cold intolerance, fatigue, dry skin, unexplained weight gain, slowed heart rate, mental and memory impairment
30
What is the treatment strategy for Hasimoto's thyroiditis?
Replacement of deficient thyroid hormone
31
What is the most common cause of hyperthyroidism?
Grave's Disease
32
Symptoms of Grave's Disease?
Heat intolerance, fatigue, sweating, weight loss, restlessness, tremors, increased HR and SBP
33
What is the treatment strategy for Graves?
Antagonism of excessive thyroid hormone by inhibiting steps in thyroid hormone synthesis and action
34
Destructive autoantibody attacks the thyroid gland, causing thyroid insufficiency and decreased synthesis and secretion of thyroid hormone...as a result, feedback inhibition on the hypothalamus and anterior pituitary gland doesn't occur, and plasma TSH levels rise?
Hashimoto's
35
What isomer of thyroxine or T4?
Levothyroxine
36
What is levothyroxine used in?
Treatment of choice for thyroid hormone replacement and TSH suppression therapy
37
What are some properties of levothyroxine?
Stable, low cost, hypoallergenic, long half-life (7 days) for one dose
38
What is an isomer of T3?
Liothyronine
39
What might be preferred in myxedema coma?
Liothyronine- Faster onset of T3 can enhance rate of recovery from life-threatening hypothyroidism
40
What is liothyronine properties?
Shorter half-life (24 hours), require multiple daily doses, higher costs, greater hormone activity, and greater risk of cardiotoxicity*
41
Why is combination therapy not superior to levothyroxine alone?
Because T4 is readily converted to T3 in tissue
42
Who does myxedema frequently occur in?
Elderly, with high incidence of underlying coronary artery disease
43
In myxedema what does low TH protect against?
Increasing O2 demand
44
If the initial dose is too high (for T4 in myxedema), what can happen?
Might precipitate angina pectoris, MI, and arrythmia
| -USE LOW INITIAL DOSE
45
In myxedema coma what do patients have before there is adequate free T4 to affect metabolism?
Patients have large pools of empty T3 and T4 binding sites what must be filled
46
What kind of patients absorb drugs poorly?
Comatose patients
47
What is myxedema coma treated with?
IV levothyroxine with initial loading dose....IV T3 may also be used, but difficult to monitor and more cardiotoxic
48
What can increase metabolism of T3 and T4, leading to hypothyroidism?
CYP inducers (rifampin and phenytoin)
49
If a drug causing hypothyroidism can't be stopped, what can be used to manage hypothyroidism?
Levothyroxine (T4)
50
What is a drug that structuralls resembles TH and contains large concentrations of iodine?
Amiodarone (anti-arrhythmic)
51
Metabolism of what releases iodine and iodide, which concentrates in the thyroid gland?
Amiodarone
52
So what can amiodarone result in?
Hypothyroidism by Wolff-Chaikoff effect
| -Autoregulatory inhibition of organification and release of TH due to elevated iodide
53
What is a common effect of levothyroxine and liothyronine?
Hyperthyroidism
54
What are CV effects of levothyroxine and liothyronine?
MI secondary to coronary spasm
55
What are MSK effects of levothyroxine and liothyronine?
Decreased bone density and hip fracture
56
What neuro effects does levothyroxine and liothyronine?
Pseudotumor cerebri (increased ICP in absence of tumor or other disease), seizure
57
What kind of disease is Grave's Disease?
Autoimmune disorder
58
What happens in Grave's Disease?
Helper T cells stimulate B cells to sythesize antibodies that activate, autonomously, the TSH receptor in the thyroid gland, resulting in sustained stimulation and increased plasma thyroid hormones....this causes suppression of TRH and TSH release--> Hyperthyroidism
59
What are labs in Grave's?
T3, T4, Free T3, Free T4 are elevated
| TSH is suppressed
60
What are 3 methods for controlling hyperthyroidism?
1. Antithyroid drug therapy
2. Surgical thyroidectomy
3. Destruction of gland with radioactive iodine
61
Who is antithyroid drug therapy good for?
Young patients with small glands and mild disease
62
What is the only therapy that leaves intact thyroid gland?
Antithyroid drug therapy
63
How long is therapy with antithyroid therapy and what is the incidence of relapse?
Long period of treatment (12-18mo)
| 50-70% incidence of relapse
64
What is the treatment of choice for very large glands or multinodular goiters?
Surgical thyroidectomy....near total removal
65
What is the preferred treatment for most patients 21 and older?
Destruction of gland with radioactive iodine
66
What are 2 antithyroid drugs that are thioamides?
Methimazole, propylthiouracil
67
What is essential for anti-thyroid activity in methimazole and propylthiouracil?
Thiocarbamide moiety
68
What is the MOA for thoamides?
Prevent TH synthesis by inhibting thyroid peroxidase, thereby blocking iodine organification and coupleing reactions
69
What is an additional thing that propylthiouracial does?
Inhibits peripheral deiodination of T4 to T4
70
When are the effects of thioamdies seen?
After 4-6 weeks, after TH stores have depleted
71
What anti-thyroid is first line for children and adults?
Methimazole
72
What adverse effect does methimazole have less of than propylthiouracil?
Liver toxicity
73
What is the onset of action and half life in methimazole?
Faster onset of action and more rapid achievement of euthyroidism and a longer half life (once daily dosing and better compliance)
74
What are 3 clinical settings where propylthiouracil is recommended?
1. Pregnant women during 1st trimester
2. Patients with life-threatening thyrotoxicosis or thyroid storm
3. Patients with adverse reactions (OTHER THAN AGRANULOCYTOSIS OR HEPATITIS) to methimazole who aren't candidates for radioiodine or surgery
75
Why is propythiouracil better during pregnancy?
It is highly bound to protein and less likely to cross the placenta
76
What should be used during 2/3 trimester of pregnancy and why?
Methimazole... due to serious liver toxicity of propylthiouracil
77
Why is propylthiouracil better for patients with life-threatening thyrotoxicosis?
The ability of propy;thiouracil to inhibit peripheral conversion of T4 to T3
78
What are common AE of methimazole and propylthiouracil?
Rash and altered sense of taste or smell (methimazole)
79
What are 2 serious AE of methimazole and propylthiouracil?
1. Agranulocytosis
| 2. Liver toxicity
80
Who is the risk of agranulocytosis increased in from methimazole and propylthiouracil?
Increased in older patients and in those receiving more than 40mg/d of methimazole
-Reversible by discontinuation
81
What can propylthiouracil cause?
Hepatic necrosis and liver failure
82
What is surgical removal of the thyroid gland?
Thyroidectomy
83
What needs to be done before thyroidectomy?
1. Treat with antithyroid drugs until euthyroid: 6 weeks
2. 10-14 days prior to surgery, give saturated solution of potassium iodide (Wolff-Chaikoff effect) to diminish vascularity of the gland to simplify surgery and reduce complications
84
What % of patients will require thyroid supplementation following near-total thyroidectomy?
80-90%
85
What inhibits organification and hormone release due to Wolff-Chaikoff effect?
Potassium Iodide
86
What can potassium iodide do?
May increase intraglandular stores of iodide--> Delay onset of thioamide therapy or prevent use of radioactive iodine therapy for several weeks
87
Why isn't potassium iodide not used alone?
Due to escape from iodide block in 2-8 weeks, resulting in severe exacerbation of thyrotoxicosis
88
Why is potassium iodide avoided in pregnancy?
Crosses placenta and causes fetal goiter
89
What is the MOA for Radioactive Iodine?
Rapidly absorbed, concentrated by the thyroid, and incorporated into storage follicles...emits B rays that destroy thyroid parenchyma
90
What are properties of radioactive iodine?
Easy oral administration, effective, low expense, absence of pain
91
Who is radioactive iodine contraindicated in and why?
Pregnant women or nursing mothers because it crosses the placenta and is excreted in breast milk...destroys fetal and infant thyroid gland
92
In patients without heart disease, how is radioactive iodine given?
Therapeutic dose is given immediately
93
In patients with heart disease, severe thyrotoxicosis, and in elderly patients, how is radioactive iodine given?
1. Treat with antithyroid drugs until euthyroid
2. Antithyroid drugs are stopped for 5-7 das
3. Administer radioactive iodine for 6-12 weeks until euthyroid or hypothyroid
4. 2nd dose may be required in some patients
5. Hypothyroidism occurs in 80% of patients...replacement with oral levothyroxine
94
What is another drug class useful for symptoms of hyperthyroidism (sweating, tremor, tachycardia)?
B-adrenergic blockers
95
What are B-adrenergic blockers used for off label with hyperthyroidism?
Therapeutic adjuncts to control SVT that often precipitates heart failure
96
What is another effect of B-adrenergic blockers that isn't clincally relevent?
Reduce peripheral conversion of T4 to T3
97
What is the current drug of choice in the Beta-Blocker family for hyperthyroisism?
Propanolol
98
What is another B-Blocker used that is B1-selective and ultra short-acting (T1/2 is 10 minutes)?
Esmolol
